DI-Tham salt of 10-cl,1,4,6,9 tetrahydro-5-methyl 4,6 dioxopyrido[3,2-g]quinoline-2,8-dicarboxylate

ABSTRACT

Novel chemical compounds of the formula: ##STR1## wherein R is selected from the group consisting of hydrogen, alkyl from one to three carbon atoms, inclusive, phenyl, alkali metal, or an amine cation; 
     X and Y can be the same or different and are selected from the group consisting of hydrogen, alkyl or from one to six carbon atoms, inclusive, cycloalkyl of 5 or 6 carbon atoms, inclusive, phenyl, hydroxyl, alkoxy having from one to three carbon atoms, inclusive, halogen, trifluoromethyl, cyano, carboxyamide and ##STR2## where Q is selected from the group consisting of hydrogen, alkyl from one to three carbon atoms, inclusive, alkali metal, and an amine cation, with the proviso that where 
     R is hydrogen, alkali metal or an amine cation, then Q is the same as R, and where 
     R is phenyl or alkyl from one to three carbon atoms, then Q is phenyl or alkyl from one to three carbon atoms; and 
     Z is selected from the group consisting of hydrogen, alkyl from one to three carbon atoms, inclusive, and phenyl. 
     The compounds are formulated with pharmaceutical carriers for oral or parenteral administration, with insufflation being the preferred method. The compositions are useful in the prophylactic treatment of sensitized humans and mammals for allergy and all anaphylactic reactions of a reagin or non-reagin mediated nature.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of co-pending divisional applicationSer. No. 531,760, filed Dec. 11, 1974, now abandoned, which is a whichis division of Ser. No. 303,971 filed Nov. 6, 1972, now abandonedcontinuation-in-part application of our copending application, Ser. No.233,772, filed on Mar. 10, 1972, now abandoned, which is acontinuation-in-part application of our copending application, Ser. No.230,034, filed on Feb. 28, 1972, now abandoned.

BRIEF SUMMARY OF THE INVENTION

This invention relates to novel compounds, pharmaceutical compositionsand a process for the prophylactic treatment of allergic conditions.

DETAILED DESCRIPTION OF THE INVENTION

In accordance with this invention, we provide compounds represented bystructure 1a ##STR3## WHEREIN IT IS UNDERSTOOD THAT 1A CAN EXIST IN ITSTAUTOMERIC FORM 1B AND THAT THE COMPOUNDS OF THIS INVENTION ARE LIKELYTO BE MIXTURES OF ALL TAUTOMERIC FORMS, THE PERCENTAGES OF EACH TAUTOMERTO BE AT LEAST PARTIALLY DEPENDENT ON THE NATURE OF R, X, Y, and Z andthe physical environment of the compound. ##STR4##

For the purpose of brevity throughout the application and appendedclaims, the compounds will be referred to hereinafter in their ketoform, structure 1a.

The R substituent is selected from the group consisting of hydrogen,alkyl from one to three carbon atoms, inclusive, phenyl, alkali metal,or an amine cation, the amine selected from the group consisting ofammonia, tris(hydroxymethyl)aminomethane,D-threo-2-amino-1-p-nitrophenyl-1,3-propanediol,N,N-bis(hydroxyethyl)-piperazine, 2-amino-2-methyl-1-propanol,2-amino-2-methyl-1,3-propanediol and2,2-bis(hydroxymethyl)-2,2',2"-nitrilotriethanol; X and Y can be thesame or different and are selected from the group consisting ofhydrogen, alkyl of from one to six carbon atoms, inclusive, cycloalkylof 5 or 6 carbon atoms, inclusive, phenyl, hydroxyl, alkoxy having fromone to three carbon atoms, inclusive, halogen, trifluoromethyl, cyano,carboxyamide and ##STR5## where Q is selected from the group consistingof hydrogen, alkyl from one to three carbon atoms, inclusive, alkalimetal, and an amine cation, the amine selected from the group consistingof ammonia, tris(hydroxymethyl)aminomethane,D-threo-2-amino-1-p-nitrophenyl-1,3-propanediol,N,N-bis(hydroxyethyl)piperazine, 2-amino-2-methyl-1-propanol,2-amino-2-methyl-1,3-propanediol and2,2-bis(hydroxymethyl)-2,2',2"-nitrilotriethanol with the proviso thatwhere R is hydrogen, alkali metal or an amine cation, the amine selectedfrom the group consisting of ammonia, tris(hydroxymethyl)aminomethane,D-threo-2-amino-1-p-nitrophenyl-1,3-propanediol,N,N-bis(hydroxyethyl)piperazine, 2-amino-2-methyl-1-propanol,2-amino-2-methyl-1,3-propanediol and2,2-bis(hydroxymethyl)-2,2',2"-nitrilotriethanol, Q is the same as R,and that where R is phenyl or alkyl from one to three carbon atoms, thenQ is phenyl or alkyl from one to three carbon atoms. The Z substituentis selected from the group consisting of hydrogen, alkyl from one tothree carbon atoms, inclusive, and phenyl.

The preferred compounds are those compounds where R is selected from thegroup consisting of hydrogen, alkali metals and an amine cation, theamine selected from the group consisting of ammonia,tris(hydroxymethyl)aminomethane,D-threo-2-amino-1-p-nitrophenyl-1,3-propanediol,N,N-bis(hydroxyethyl)piperazine, 2-amino-2-methyl-1-propanol,2-amino-2-methyl-1,3-propanediol and2,2-bis(hydroxymethyl)-2,2',2"-nitrilotriethanol X and Y are the same ordifferent and are selected from the group consisting of hydrogen, alkylfrom one to three carbon atoms, inclusive, phenyl, hydroxyl, halogen,alkoxy having from one to three carbon atoms, inclusive,trifluoromethyl, cyano, carboxyamide and ##STR6## where Q is selectedfrom the group consisting of hydrogen, alkali metal, and an aminecation, the amine selected from the group consisting of ammonia,tri(hydroxymethyl)aminomethane,D-threo-2-amino-1-p-nitrophenyl-1,3-propanediol,N,N-bis(hydroxyethyl)piperazine, 2-amino-2-methyl-1-propanol,2-amino-2-methyl-1,3-propanediol and2,2-bis(hydroxymethyl)-2,2',2"-nitrilotriethanol with the proviso that Qis the same as R. Z is selected from the group consisting of hydrogenand alkyl from one to three carbon atoms, inclusive.

The more preferred compounds are those compounds where R is selectedfrom the group consisting of alkali metal and an amine cation, the amineselected from the group consisting of ammonia,tris(hydroxymethyl)aminomethane,D-threo-2-amino-1-p-nitrophenyl-1,3-propanediol,N,N-bis(hydroxyethyl)piperazine, 2-amino-2-methyl-1-propanol, propanol,2-amino-2-methyl-1,3-propanediol and2,2-bis(hydroxymethyl)-2,2',2"-nitrilotriethanol; X and Y can be thesame or different and are selected from the group consisting of alkylfrom one to three carbon atoms, inclusive, alkoxy having one to threecarbon atoms, inclusive, halogen, cyano, ##STR7## where Q is selectedfrom the group consisting of alkali metal and an amine cation, the amineselected from the group consisting of ammonia,tris(hydroxymethyl)aminomethane,D-threo-2-amino-1-p-nitrophenyl-1,3-propanediol,N,N-bis(hydroxyethyl)piperazine, 2-amino-2-methyl-1-propanol,2-amino-2-methyl-1,3-propanediol and2,2-bis(hydroxymethyl-2,2',2"-nitrilotriethanol with the proviso that Qis the same as R. Y is hydrogen. Z is hydrogen.

The most preferred compounds are those compounds where R is an alkalimetal or an amine cation, the amine selected from the group consistingof ammonia, tris(hydroxymethyl)aminomethane,D-threo-2-amino-1-p-nitrophenyl-1,3-propanediol,N,N-bis(hydroxyethyl)piperazine, 2-amino-2-methyl-1-propanol,2-amino-2-methyl-1,3-propanediol and2,2-bis(hydroxymethyl)-2,2',2"-nitrilotriethanol; X is selected from thegroup consisting of fluoro, chloro, methyl, ethyl, cyano, methoxy,ethoxy, and ##STR8## where Q is selected from the group consisting ofalkali metal and an amine cation, the amine selected from the groupconsisting of ammonia, tris(hydroxymethyl)aminomethane,D-threo-2-amino-1-p-nitrophenyl-1,3-propanediol,N,N-bis(hydroxyethyl)piperazine, 2-amino-2-methyl-1-propanol,2-amino-2-methyl-1,3-propanediol and2,2-bis(hydroxymethyl)-2,2',2"-nitrilotriethanol, with the proviso thatQ is the same as R, and Y is selected from the group consisting ofhydrogen, methyl, nitrile, and ##STR9## where Q is selected from thegroup consisting of alkali metal, and an amine cation, the amineselected from the group consisting of ammonia,tris(hydroxymethyl)aminomethane,D-threo-2-amino-1-nitrophenyl-1,3-propanediol,N,N-bis(hydroxyethyl)piperazine,2-amino-2-methyl-1-propanol-2-amino-2-methyl-1,3-propanediol and2,2-bis(hydroxymethyl)-2,2',2"-nitrilotriethanol with the proviso that Qis the same as R; and Z is hydrogen.

As employed in the above disclosure and throughout the specification,the term "halogen" includes fluoro, chloro, bromo, and iodo and the term"alkyl" includes methyl, ethyl, propyl, and isopropyl when limited tothree carbon atoms and includes butyl, isobutyl, tertbutyl, pentyl,isopentyl, neopentyl, hexyl, isohexyl, and 3-dimethylbutane when limitedto six carbon atoms. "Alkali metal" includes sodium and potassium. Thecompounds of this invention can be prepared by methods known to the art.The basic synthetic pathway employed is the reaction of an appropriatelysubstituted m-diaminobenzene (II) with an oxaloacetate sodium salt (III)in the presence of a solvent to form the diadduct (IV). The R group islimited to the alkyl group of from one to three carbon atoms, inclusive,and phenyl. Ring closure to the desired compound (1a) is accomplished byheating the diadduct at appropriate conditions. ##STR10##

After the above synthesis has been carried out, the carboxylate can betransesterified to other esters or hydrolyzed to the carboxy acid. Thecarboxy acid is converted to the alkali metal or amine salts by standardmethods.

X and Y substituted metal diaminobenzene starting materials have beenprepared in the art prior to this invention. Furthermore, a substantialnumber of X and Y substituted m-dinitrobenzenes are known. These nitrogroups can be easily reduced to amino groups by various methodsincluding the use of iron and acetic acid, catalytic hydrogenation inthe presence of platinum or palladium, or stannous chloride andconcentrated hydrochloric acid.

Included among starting materials made available by the art are thefollowing substituted benzene compounds: ##STR11##

                  TABLE I                                                         ______________________________________                                        X         Y          X           Y                                            ______________________________________                                        CH.sub.3  H          C.sub.2 H.sub.5                                                                           H                                            Cl        H          OH          H                                            OCH.sub.3 H          CH.sub.3    COOH                                         OC.sub.2 H.sub.5                                                                        H          Cl          CH.sub.3                                     CH.sub.3  CH.sub.3   Cl          COOH                                         Cl        CH.sub.3   COOH        H                                            C.sub.2 H.sub.5                                                                         H          CN          H                                                                 F           H                                                                 Br          H                                                                 I           H                                                                 OC.sub.2 H.sub.5                                                                          CH.sub.3                                                          C.sub.3 H.sub.7                                                                           H                                                                 OC.sub.3 H.sub.7                                                                          H                                                                 H           OCH.sub.3                                                         H                                                                             H           CH                                                                OH          OH                                                                H           I                                                                 CH.sub.3    COOH                                                              CH.sub.3    CH.sub.3                                                          CH.sub.3    OC.sub.2 H.sub.5                                                  OH          C.sub.3 H.sub.7                                                   OH          I                                                                 H           C.sub.3 H.sub.7                                                   C.sub.2 H.sub.5                                                                           CH.sub.3                                                          CH.sub.3    C.sub.2 H.sub.3                              ______________________________________                                    

Other diamino starting materials are readily synthesized from availablecompounds. For example, o-dinitrotrimethylfluorobenzene is prepared byreacting o-dinitrobenzoic acid with sulfur tetrafluoride.

The second reactant, the oxaloacetate derivative is also readilyavailable. Compounds where R is ethyl and Z is hydrogen, ethyl or phenylare known in the art and isopropyl is easily prepared.

Where Z is hydrogen, an alternative reagent to the oxaloacetatederivative is available to form the diadduct. Acetylene dicarboxylate(V), where R is limited to alkyl of from one to three carbon atoms,inclusive, or phenyl, can be added to the diaminobenzene derivative toform the diadduct (IV) as illustrated below: ##STR12##

In the formation of the diadduct and subsequent ring closure, thefollowing processing conditions can be observed.

When using the oxaloacetate reagent to form the diadduct, there shouldbe a sufficient amount of acid present to protonate the oxaloacetatecarbanion and catalyze the removal of the keto grouping as water. Theacid can also serve as a solvent for the two reagents as well. Forexample, glacial acetic acid, propionic acid, p-toluene sulfonic acid,and butyric acid are acids which can be used. If a further reagent isneeded to place the two reactants into solution, (or a cosolventdesired), benzene, toluene, diethyl ether, dioxane, tetrahydrofuran, oralcohols from one to about four carbon atoms can be employed. The lengthof time for the formation of the diadduct is temperature dependent. Atroom temperature the reaction proceeds rather slowly but as thetemperature is raised, reaction time is decreased. Acceptable reactiontimes are achieved at temperatures ranging from about 40° to about 70°C., although reaction temperatures can be above 100° C. if desired.

With regard to the use of the acetylene dicarboxylate reactant in theformation of the diadduct, appropriate solvents are alcohols having fromone to about six carbon atoms, preferably one to about three carbonatoms, benzene, diethylether, dioxane, tetrahydrofuran, or any othersolvent which places both of the reactants in solution and allows thedesired compound to form. Generally the reaction proceeds readily atroom temperature and can be promoted by an increase in temperature toabout 100° C.

Ring closure of the diadduct, prepared by the methods disclosed above,and formation of the desired compound can be accomplished by heating thediadduct at a relatively high temperature. This heating can be done tothe neat diadduct. However, it is preferred to use a solvent which canfunction as a heat transfer medium. Any high boiling inert solvent suchas a mineral oil, hexamethylphosphoric triamide, diphenyl ether, orDowtherm A®, which appears to be primarily a diphenyl ether side productof the Dow Chemical Company preparation of phenol, is suitable. The ringcyclization step is preferably carried out at temperatures of from about220° C. to about 280° C., although lower or higher temperatures can beemployed if desired. A particularly preferred solvent is Dowtherm A®,which boils at 250° C., thus enabling the ring cyclization to occurduring reflux.

An additional advantage of the elevated temperature during the ringcyclization step is that any adduct formed in the preceding step whichis not in a position to cyclize since it is trans to the benzene ring isisomerized to the cis configuration during heating, thereby allowingsubstantial yields of the desired compound to be produced. This transadduct preparation occurs more frequently when a non-polar solvent andacetylene dicarboxylate are used in the adduct formation step.

The desired compound is isolated and crystallized by conventionalmethods. Isomers of the desired product are generally insignificant.However, when X and Y are both hydrogen or X is hydrogen and Y can becertain groups such as methyl, chlorine, or cyano, ring cyclization canpossibly occur at the X position as well as at the desired positions.However, these isomeric mixtures can be resolved using standardtechniques. For example, where X is hydrogen, an isomeric mixture can bereadily separated using silica gel or alumina as the chromatographicsupport and a mixture of methylene chloride and methanol as the eluant.In cases wherein the desired compound is prepared in very poor yield orthe mixture components are difficult to separate, an alternate route forthe preparation of the desired compound is the preparation of a compoundwherein X is halogen, preferably chlorine, followed by hydrogenationover a palladium/charcoal catalyst. This treatment replaces the halogenwith hydrogen, thereby preparing the compound which is desired.

As stated previously, at this point various esters, the acid, or saltscan be prepared at the R position of the carboxy group. Different esterscan be prepared by standard transesterification reaction. Ester groupsare converted to the acid by treatment with base and acid. The acid canthen be easily converted to the amine or alkali metal salts bycontacting the diacid with two equivalents of the desired amine oralkali metal and heating in a sufficient amount of water to effectsolubilization. The crystalline salts can be precipitated by theaddition of methanol. When R is hydrogen, alkali metal, or amine cation,and X or Y is COOQ, then Q is the same as R.

Following is an illustrative list of reactants and desired compoundswhich can be prepared by the above disclosed procedures:

                                      TABLE III                                   __________________________________________________________________________    Starting Materials        Product                                              ##STR13##                                                                                               ##STR14##                                                  X             Y              R                                        __________________________________________________________________________            H             H              CH.sub.3                                         H             CH.sub.3       CH.sub.3                                         H             C.sub.2 H.sub.5                                                                              CH.sub.3                                         H             iC.sub.3 H.sub.7                                                                             CH.sub.3                                         H             iC.sub.4 H.sub.9                                                                             CH.sub.3                                         H             iC.sub.5 H.sub.11                                                                            CH.sub.3                                         H             2,3-dimethyl-  CH.sub.3                                                       butane                                                          iC.sub.3 H.sub.7                                                                            H              CH.sub.3                                         CH.sub.3      CH.sub. 3      CH.sub.3                                         C.sub.2 H.sub.5                                                                             tC.sub.4 H.sub.0                                                                             CH.sub.3                                         neopentyl     C.sub.3 H.sub.7                                                                              CH.sub.3                                         nC.sub.6 H.sub.13                                                                           C.sub.2 H.sub.5                                                                              C.sub.2 H.sub.5                                  iC.sub.3 H.sub.7                                                                            C.sub.5 H.sub.9                                                                              C.sub.2 H.sub.5                                  C.sub.5 H.sub.11                                                                            C.sub.2 H.sub.5                                                                              C.sub.2 H.sub.5                                  C.sub.6 H.sub.5                                                                             OH             C.sub.2 H.sub.5                                  OH            iC.sub.2 H.sub.7                                                                             C.sub.2 H.sub.5                                  OH            OH             C.sub.2 H.sub.5                                  OH            H              C.sub.2 H.sub.5                                  OH            OC.sub.2 H.sub.5                                                                             C.sub.2 H.sub.5                                  OiC.sub.3 H.sub.7                                                                           OH             C.sub.2 H.sub.5                                  OH            Br             C.sub.2 H.sub.5                                  OH            CF.sub.3       C.sub.2 H.sub.5                                  CN            OH             C.sub.3 H.sub.7                                  OH            iC.sub.5 H.sub.11                                                                            C.sub.3 H.sub.7                                  OH            C.sub.3 H.sub.7                                                                              C.sub.3 H.sub.7                                  CONH.sub.2    OH             C.sub.3 H.sub.7                                  OH            COOC.sub.2 H.sub.5                                                                           C.sub.3 H.sub.7                                  COOCH.sub.3   OH             C.sub.3 H.sub.7                                  C.sub.2 H.sub.5                                                                             C.sub.6 H.sub.5                                                                              C.sub.3 H.sub.7                                  OCH.sub.3     F              C.sub.3 H.sub.7                                  l             OC.sub.2 H.sub.5                                                                             C.sub.3 H.sub.7                                  OC.sub.3 H.sub.7                                                                            CF.sub.3       C.sub.3 H.sub.7                                  CN            OiC.sub.3 H.sub.7                                                                            C.sub.3 H.sub.7                                  OC.sub.2 H.sub.5                                                                            CONH.sub.2     iC.sub.3 H.sub.7                                 CONH.sub.2    OCH.sub.3      iC.sub.3 H.sub.7                                 Cl            CF.sub.3       iC.sub.3 H.sub.7                                 CN            Br             iC.sub.3 H.sub.7                                 l             CONH.sub.2     iC.sub.3 H.sub.7                                 F             COOCH.sub.3    iC.sub.3 H.sub.7                                 Cl            Cl             iC.sub.3 H.sub.7                                 OC.sub.2 H.sub.5                                                                            OCH.sub.3      iC.sub.3 H.sub.7                                 CF.sub.3      CN             iC.sub.3 H.sub.7                                 CONH.sub.2    CF.sub.3       iC.sub.3 H.sub.7                                 CF.sub.3      COOC.sub.3 H.sub.7                                                                           iC.sub.3 H.sub.7                                 CN            CN             C.sub.6 H.sub.5                                  CONH.sub.2    CN             C.sub.6 H.sub.5                                  CN            COOC.sub.2 H.sub.5                                                                           C.sub.6 H.sub.5                                  CONH.sub.2    COOCH.sub.3    C.sub.6 H.sub.5                                  COOC.sub.3 H.sub.7                                                                          COOCH.sub.3    C.sub.6 H.sub.5                                  F             H              C.sub.6 H.sub.5                                  Cl            H              C.sub.6 H.sub.5                                  CH.sub.3      H              C.sub.6 H.sub.5                                  C.sub.2 H.sub.5                                                                             H              C.sub.6 H.sub.5                                  CN            H              C.sub.6 H.sub.5                                  OCH.sub.3     H              C.sub.6 H.sub.5                                  OC.sub.2 H.sub.5                                                                            H              CH.sub.3                                         COOCH.sub.3   H              C.sub.2 H.sub.5                                  F             Me             C.sub.3 H.sub.7                                  Cl            Me             iC.sub.3 H.sub.7                                 C.sub.2 H.sub.5                                                                             Me             CH.sub.3                                         CN            Me             C.sub.2 H.sub.5                                  OCH.sub.3     Me             C.sub.3 H.sub.7                                  OC.sub.2 H.sub.5                                                                            Me             iC.sub.3 H.sub.7                                 COOC.sub.2 H.sub.5                                                                          Me             CH.sub.3                                         F             CN             C.sub.2 H.sub.5                                  Cl            CN             C.sub.3 H.sub.7                                  CH.sub.3      CN             iC.sub.3 H.sub.7                                 C.sub.2 H.sub.5                                                                             CN             CH.sub.3                                         CN            CN             C.sub.2 H.sub.5                                  OCH.sub.3     CN             C.sub.3 H.sub.7                                  OC.sub.2 H.sub.5                                                                            CN             iC.sub.3 H.sub.7                                 COOC.sub.2 H.sub.5                                                                          CN             CH.sub.3                                         F             COOCH.sub.3    C.sub.2 H.sub.5                                  Cl            COOC.sub.2 H.sub.5                                                                           C.sub.3 H.sub.7                                  CH.sub.3      COOC.sub.3 H.sub.7                                                                           iC.sub.3 H.sub.7                                 C.sub.2 H.sub.5                                                                             COOCH.sub.3    CH.sub.3                                         CN            COOC.sub.2 H.sub.5                                                                           C.sub.2 H.sub.5                                  OCH.sub.3     COOC.sub.3 H.sub.7                                                                           C.sub.3 H.sub.7                                  OC.sub.2 H.sub.5                                                                            COOCH.sub.3    iC.sub.3 H.sub.7                                 COOC.sub.3 H.sub.7                                                                          COOC.sub.2 H.sub.5                                                                           CH.sub.3                                 __________________________________________________________________________

table iii

the above illustrative examples can be prepared where Z in theoxaloacetate sodium salt is methyl, ethyl, propyl, isopropyl, andphenyl, as well as where Z is hydrogen.

TABLE IV

The illustrative examples of Tables II and III can be converted tocompounds where R is selected from the group consisting of hydrogen, analkali metal or an amine cation, the amine selected from the groupconsisting of ammonia, tris(hydroxymethyl)aminomethane,D-threo-2-amino-1-p-nitrophenyl-1,3-propanediol,N,N-bis(hydroxyethyl)piperazine,2-amino-2-methyl-1-propanol,2-amino-2-methyl-1,3-propanediol and2,2-bis(hydroxymethyl)-2,2',2"-nitrilotriethanol by standard methods.

For the sake of brevity, Tables III and IV are not rendered in the samemanner as Table II but the same illustrative scoping is intended.

The following compounds are prepared in accordance with our invention.These compounds are not meant to limit but merely to exemplify theinvention.

EXAMPLE 1 -- Dimethyl1,4,6,9-tetrahydro-10-methyl-4,6-dioxopyrido[3,2-g]quinoline-2,8-dicarboxylate

30.0 g. of dimethylacetylene dicarboxylate is added dropwise to asolution of 12.2 g. of 2,6-diaminotoluene in 200 ml. methanol at roomtemperature. The reaction mixture is stirred at room temperature for onehour during which time the yellow product, a 1:2 adduct, precipitatesand 24.8 g. is collected by filtration. An additional 10 g. of theproduct is obtained by stirring the filtrate for 24 hours. 5.0 g. of the1:2 adduct is added to ca 250° refluxing Dowtherm A® and the mixture isheated at the reflux temperature. Upon cooling, the yellow crystallineproduct precipitates and 3.3 g. are recovered. The compound isrecrystallized from methanol-chloroform. The melting point is291.5°-292.5° dec.

Anal. Calcd. for: C₁₇ H₁₄ O₆ N₂ : C, 59.65; H, 4.12; N, 8.18. Found: C,58.83; H, 4.13; N, 7.94. UV (ethanol) λmax 219 (ε 20,050), 227 sh(17,800), 257 (62,550), 276 sh (18,400) 290 sh (10,450), 315 sh (3,600),357 (7,700), 375 (13,650) and 405 (9,450). IR (nujol) 3400, 1734, 1640,1610, 1590, 1510, 1265, 1160, 1020, 1010, 930, 865, 785.

EXAMPLE 2 -- Diethyl1,4,6,9-tetrahydro-10-methyl-4,6-dioxopyrido[3,2-g]quinoline-2,8-dicarboxylate

A mixture of 12.2 g. 2,6-diaminotoluene, 42 g. of the sodium salt ofdiethyloxaloacetate, and 100 ml. of glacial acetic acid is heated at 50°C. for 4 hours and is then allowed to stand at room temperature for 18hours. The mixture is poured into ice water and made basic to pH 8 with35% aqueous sodium hydroxide. The resulting solution is extracted withether three times with a 200 ml. portion and four times with 200 ml. of0.5 N sodium hydroxide. It is then dried with anhydrous sodium sulfateand the solvent removed. A brown oil solidifies upon standing.Recrystallization from Skellysolve B gives the diethyl diadduct asyellow needles. This adduct is added to boiling Dowtherm A® and thecompound isolated.

EXAMPLE 3 -- Disodium1,4,6,9-tetrahydro-10-methyl-4,6-dioxopyrido[3,2-g]quinoline-2-8-dicarboxylate

Either of the products of Example 1 or 2 is treated with 5% aqueoussodium hydroxide at reflux for 1.5 hours and the solution cooled. Thesodium salt is recovered.

EXAMPLE 4 --1,4,6,9-tetrahydro-10-methyl-4,6-dioxopyrido[3,2-g]quinoline-2,8-dicarboxylicacid

The cooled solution of Example 3 is acidified with concentrated HCl andthe dicarboxy acid precipitates as a bright yellow crystalline solid.The product is collected by filtration, washed with water and dried atreduced pressure at 60° C. It has a melting point greater than 310° C.

EXAMPLE 5 -- Di(tris-hydroxymethyl)methylammonium1,4,6,9-tetrahydro-10-methyl-4,6-dioxopyrido[3,2-g]quinoline-2,8-dicarboxylate

1.0 g. of the dicarboxylic acid prepared in Example 4 is added to 10 ml.of water. 0.77 g. of tris(hydroxymethyl)aminomethane is added. Themixture is heated for several minutes until solution is complete. Thecrystalline amine salt is precipitated with the addition of methanol.

EXAMPLE 6 --Dimethyl-10-chloro-1,4,6,9-tetrahydro-4,6-dioxopyrido[3,2-g]quinoline-2,8-dicarboxylate

A solution of 1 ml. of concentrated hydrochloric acid in 5 ml. of 5%ethanol is slowly added to a refluxing mixture of 10.1 g. of1-chloro-2,6-dinitrobenzene, electrolytically reduced iron and 20 ml. of50% ethanol. The mixture is heated at reflux for two hours. The mixtureis allowed to cool slightly and the pH is adjusted to 8 with sodiumhydroxide solution. The iron products are removed by filtration. Thesolvent is removed from the filtrate to leave a solid which is dissolvedin water and extracted with methylene chloride. Removal of the solventsleaves an oily solid which upon recrystallization of from Skellysolve Bgives off-white crystals of 2-chloro-1,3-diaminobenzene having a meltingpoint of 82°-83.5° C.

11.0 g. of dimethylacetylene dicarboxylate is added dropwise to asolution of 5.25 g. of 2-chloro-1,3-diaminobenzene in 100 ml. ofmethanol at room temperature. The mixture is stirred for two hours atroom temperature and the resulting yellow solid is collected byfiltration. The solid is washed with 20 to 50 ml. of methanol, driedunder vacuum at 60° C., and recrystallized from acetone. Thetetramethyl[2-chloro-m-phenylene-diamino]dimaleate melts at202.5°-204.5° C.

Anal. Calcd. for: C₁₈ H₁₉ O₈ N₂ Cl: C, 50.54; H, 4.49; N, 6.56; Cl,8.31. Found: C, 50.38; H, 4.44; N, 6.86; Cl, 8.45. UV (ethanol) max 226(ε 19,200), 327 (28,000). IR (nujol) NH 3270, C-O 1735, 1670.

9.35 g. tetramethyl[(2-chloro-m-phenylene)diamino]-dimaleate is added to125 ml. of Dowtherm A® refluxing at about 255° C. over a period of fiveminutes. The mixture is refluxed for an additional five minutes and thencooled to room temperature. The resulting yellow solid is filtered,washed with acetone and dried. Recrystallization from a 1:1 mixture ofmethylene dichloride and methanol gives yellow needles having a meltingpoint of 266°-267° C.

Anal. Calcd. for: C₁₆ H₁₁ O₆ N₂ Cl: C, 53.07; H, 3.06; N, 7.74; Cl,9.79. Found: C, 53.04; H, 3.07; N, 7.83; Cl, 9.86.

UV (ethanol) λmax 214 (ε 18,750), 230 sh (18,800), 243 (51,950), 290 sh(12,000), 295 sh (9,700), 210 sh (3,550), 360 sh (8,660), 379 (14,650),400 sh (8,600). IR (Nujol) 3360, 1745. Mass spec. 362 mol. ion.

EXAMPLE 7 --10-chloro-1,4,6,9-tetrahydro-4,6-dioxopyrido[3,2-g]quinoline-2,8-dicarboxylicacid

1.05 g. of the diester compound prepared in Example 6 is heated atreflux for 1 hour in 20 ml. of 5% sodium hydroxide. The mixture iscooled, 10 ml. of water added, and the pH adjusted to 3 withconcentrated hydrochloric acid. The bright yellow diacid is collected byfiltration. It has a melting point greater than 310° C.

EXAMPLE 8 -- Disodium10-chloro-1,4,6,9-tetrahydro-4,6-dioxopyrido[3,2-g]quinoline-2,8-dicarboxylate

The diacid prepared in Example 7 is dissolved in hot 4% sodiumbicarbonate. Upon cooling, the disodium salt precipitates and iscollected by filtration. Recrystallization from water gives a yellowsolid melting above 310° C.

Anal. Calcd. for: C₁₄ H₅ O₆ N₂ ClNa₂ : C, 44.41; H, 1.33; N, 7.40; Cl,9.36. Found: C, 44.05; H, 1.30; N, 7.24; Cl, 9.33.

UR (H₂ O) λmax 214 (ε 21,150), 259 (65,800), 296 sh (4,750), 305 sh(3,000), 350 sh (5,750), 367 (9,500), 395.5 (9,950), 409 (10,950); IR(nujol) 3310, 1705, 1675, 1650, 1630, 1600, 1575, 1505.

EXAMPLE 9 -- Di(tris-hydroxymethyl)methylammonium10-chloro-1,4,6,9-tetrahydro-4,6-dioxopyrido[3,2-g]quinoline-dicarboxylate

A solution of 4.0 g. disodium10-chloro-1,4,6,9-tetrahydro-4,6-dioxopyrido[3,2-g]quinoline-2,8-dicarboxylatedissolved in 100 ml. of water is acidified with concentrated HCl to givethe desired diacid as a yellow crystalline solid. The product iscollected by filtration and dried. The diacid is converted to the disaltby adding 4.0 g. tris(hydroxymethyl)aminomethane and dissolving themixture in 15 ml. of water to which 200 ml. of methanol is added. Themixture is allowed to stand 18 hours at room temperature. The yellowcrystalline product is collected by filtration, washed well withmethanol and dried. It has a melting point greater than 310° C., withsintering at 250°.

Anal. UV (H₂ O) 214 mu (ε 23,250), 259 (ε 71,200), 284 sh (ε 11,150),409 (ε 12,150). IR (nujol) λmax 3320, 3300-3100 (broad); 1625 (broad);1570 sh. 1490, 1340, 1255, 1060, 805, 790.

EXAMPLE 10 --Di(tris-hydroxymethyl)methylammoniumpyrido[3,2-g]quinoline-2,8-dicarboxylate

To a solution of 5 gm. of di(tris-hydroxymethyl) methylammonium10-chloro-1,4,6,9-tetrahydro-4,6-dioxopyrido[4,3-g]quinoline-2,8-dicarboxylatein 100 ml. of water is added 2.0 g. of 5% palladium-on-charcoal catalystand 5.0 g. of magnesium oxide. The resulting mixture is hydrogenated atan initial pressure of 3 atmospheres of hydrogen until 1 mole ofhydrogen has been absorbed. The mixture is filtered and the filtrateacidified by the addition of dilute hydrochloric acid. The resultingprecipitate is removed by filtration. The1,4,6,9-tetrahydro-4,6-dioxopyrido[3,2-g]quinoline-2,8-dicarboxylic acidobtained is converted to di(tris-hydroxymethyl)methylammonium1,4,6,9-tetrahydro-4,6-dioxopyrido[3,2-g]quinoline-2,8-dicarboxylate byadding two equivalents of (tris-hydroxymethyl)methylamine in aqueoussolution. The crystalline product is recovered after addition ofmethanol.

EXAMPLE 11 --10-Chloro-1,4,6,9-tetrahydro-4,6-dioxo-5-(trifluoromethyl)pyrido[3,2-g]quinoline-2,8-dicarboxylicacid a. 2-Chloro-5-α,α,α-trifluoromethyl-m-phenylenediamine

To a stirred solution of 90.24 grams (0.4 mole) of stannous chloridedihydrate in 220 ml. of concentrated HCl is added, portionwise, 15.22grams [0.0564 mole] of 3.5-dinitro-4-chlorobenzotrifluoride obtainedfrom Pierce Chem. Co. The mixture is warmed to 60°, stirred, and allowedto cool to room temperature and then stirred at room temperature forfive hours and allowed to stand over night.

To the mixture is added slowly, with cooling, a 50% solution of sodiumhydroxide until the mixture is strongly basic. The insoluble material isremoved by filtration, dissolved in water and washed well with methylenechloride. The filtrate is extracted with additional CH₂ Cl₂. Themethylene chloride extracts are dried over anhydrous MgSO₄ and thesolvent removed. The combined solid is recrystallized fromethanol-water. There is obtained 9.02 grams melting at 95.6°.

b. Dimethyl10-chloro-1,4,6,9-tetrahydro-4,6-dioxo-5-(trifluoromethyl)pyrido[3,2-g]-quinoline-2,8-dicarboxylate

To a solution of 8.52 grams (0.0404 mole) of2-chloro-5-α,α,α-trifluoromethyl-m-phenylenediamine in 140 ml. ofmethanol is added dropwise, with stirring, 11.93 grams (0.084 mole) ofdimethyl acetylene dicarboxylate. Stirring is continued for five hours.The yellow precipitate is removed by filtration. There is obtained 6.40grams of material melting at 205°-8°. Evaporation of the filtrate givesan additional 6.10 grams of material melting at 203°-6°.

To a refluxing mixture of 100 ml. of Dowtherm A is added 9.88 grams ofthe material obtained above. Refluxing is continued for thirty minutes.The mixture is cooled to room temperature, the precipitate removed byfiltration and washed with Skellysolve B and then boiled with ethanol.The mixture is allowed to cool and the solid removed by filtration.There is obtained 2.29 grams of material melting at 273° (dec.).

Analysis for: C₁₇ H₁₀ ClF₃ N₂ O₆ Calcd.: C, 47.40; H, 2.34; Cl, 8.23; F,13.23; N, 6.51%. Found: C, 48.02; H, 2.40; Cl, 7.71; F, 13.43; N, 6.66%.The IR spectra is in agreement.

c. Product

A mixture of 1.65 grams (0.0058 mole) of dimethyl10-chloro-1,4,6,9-tetrahydro-4,6-dioxo-5-(trifluoromethyl)pyrido[3,2-g]quinoline-2,8-dicarboxylateand 20 ml. of water is stirred and to the mixture is added a 5% sodiumhydroxide solution until solution occurs (3 ml.). The solution isstirred for 15 minutes and then acidified by the addition of a diluteHCl solution. The resulting tan precipitate is removed by filtration andwashed with water. There is obtained 1.11 gram of material melting above300°.

Anal. Calcd. for C₁₅ H₆ ClF₃ N₂ O₆ : F, 14.16% Found: F, 13.95%.

EXAMPLE 12 --1,4,6,9-Tetrahydro-4,6-dioxopyrido[3,2-g]-quinoline-2,8,10-tricarboxylicacid a. Methyl 2,6-dinitrobenzoate

2,6-Dinitrobenzoic acid (10.6 grams) is suspended in ether (125 ml.) at0° C. 1-Methyl-3-p-tolyltriazene (8.2 grams) in ether (75 ml.) is addeddropwise to the stirred reaction mixture in an ice bath. the reactionmixture is stirred at 0° for one hour and at room temperature for onehour. The reaction mixture is diluted to 1 l. with ether and theinsoluble product collected by filtration. Recrystallization frommethanol gives colorless crystals (3.65 grams, melting point150°-151.5°). An additional 4.1 grams of product are obtained from thefiltrate.

Analysis: Calcd.: C, 42.49; H, 2.67; N, 12.39. Found: C, 42.55; H, 2.74;N, 12.10. ir (nujol): CH 3090; C═O, 1735; NO₂, 1350. uv (EtOH): λ_(max)(ε) 233 (15,900), 295 sh (984).

b. Tetramethyl 2,2'-(2-carbomethoxyphenylene-1,3-diimino)dibutenedioate

Methyl 2,6-dinitrobenzoate (7.75 grams) is dissolved in methanol (250ml.) and treated with 10% palladium on charcoal (0.8 gram) and hydrogen(40 psi) on a Parr Hydrogenator for two hours. The catalyst is removedby filtration and dimethyl acetylenedicarboxylate (15.0 grams) addedslowly. The reaction mixture is allowed to stir at room temperature foreighteen hours. The 1:2 adduct is collected by filtration (11.7 grams,melting point 147°-149°).

Analysis: Calcd.: C, 53.33; H, 4.92; N, 6.22. Found: C, 53.28; H, 4.93;N, 6.09. ir (Nujol): NH, 3290, 3210; C═O 1735, 1724, 1685; C═C/C═N,1605, 1580; aromatic CH 805. uv (EtOH): λ_(max) (ε) 205 (17,400), 232(18,800), 311 (21,900), 352 (24,200).

c. Trimethyl1,4,6,9-tetrahydro-4,6-dioxopyrido[3,2-g]quinoline-2,8-10-tricarboxylate

The 1:2 adduct (10.0 grams) is added to refluxing Dowtherm A. Thereaction mixture is refluxed for seven minutes and then allowed to coolto room temperature. The yellow triester is collected by filtration, andwashed with acetone and twice with hot chloroform. The insoluble solidis homogeneous by thin layer chromatography (2.67 grams, melting point282°-286° dec.).

Analysis: ir (Nujol): NH/OH 3320, 3200, 3080; C═O 1760, 1725, 1695;aromatic CH 805, 780. uv (MeOH): λ_(max) (ε) 210 (26,800), 226 sh(20,000), 257 (52,900), 397 sh (19,700), 409 (21,300).

d. Product

The triester (1.0 gram) is dissolved in 1.0 N sodium hydroxide (15 ml.).After stirring for a few minutes, the sodium salt precipitates. Thissolid is collected and dissolved in water and the pH adjusted to pH=3with 3M hydrochloric acid. The solid diacid is collected by filtration,washed with water, and dried in a vacuum oven (1.0 gram, melting point >320°).

Analysis: ir (Nujol): OH/NH 3480, 3270; ═CH 3080, C═O 1725 uv (H₂ O):λ_(max) (ε) 214 (22,100), 219 sh (21,350), 264 (48,500), 286 sh (7,550),298 sh (2,300), 387 (12,700), 408 (10,500), 427 (11,350).

EXAMPLE 13 --10-Chloro-1,4,6,9-tetrahydro-5-methyl-4,6-dioxopyrido[3,2-g]quinoline-2,8-dicarboxylicacid a. 4-Chloro-3,5-toluenediamine

3,5-Dinitro-4-chlorotoluene (100 grams) is dissolved in ethanol (165ml.) and 125 ml. of water is added slowly to the refluxing mixture.Ethanol is added from time to time to insure complete solution.Electrolytically reduced iron powder (167 grams) is added to thereaction mixture. A solution of concentrated hydrochloric acid (10 ml.)in 1:1 ethanol-water (50 ml.) is added carefully. The reaction mixtureis refluxed for two hours, cooled slightly, and the pH adjusted to pH=8with 20% sodium hydroxide. The inorganic precipitate is removed byfiltration and the filtrate evaporated to leave dark solid. The solid ispartially dissolved in benzene and the remaining inorganic matterremoved. The filtrate is evaporated to dryness and the desired diamineis isolated by extraction from the residue with Skellysolve B.Recrystallization from Skellysolve B gives tan plates (54.2 grams,melting point 115°-116°).

Analysis for: C₇ H₉ N₂ Cl Calcd.: C, 53.71; H, 5.97; N, 17.90; Cl,22.66. Found: C, 53.82; H, 5.76; N, 18.27; Cl, 22.70. ir (Nujol): NH3410, 3350, 3300, 3180; NH/C═C 1610, 1595 sh, 1490; aromatic CH/C-Cl840, 825, 815. uv (EtOH): λ_(max) (ε) 217 (38,500), 246 sh (7,250) 293(1,900).

b. Tetramethyl 2,2'-(2-chlorotoluene-3,5-diimino)dibutenedioate

4-Chloro-3,5-toluenediamine (35 grams) is dissolved in methanol (500ml.) and dimethyl acetylenedicarboxylate (75 grams) is added slowly. Thereaction mixture is stirred for 18 hours and the resulting solid 1:2adduct is collected by filtration (54.35 grams, melting point 209°-11°).Recrystallization from acetone gives a crystalline solid (mp.216.5°-218°).

Analysis for: C₁₉ H₂₁ O₈ N₂ Cl Calcd.: C, 51.76; H, 4.80; N, 6.36; Cl,8.04. Found: C, 51.71; H, 4.81; N, 6.07; Cl, 8.00. ir (Nujol): NH 3250,C═O 1740, 1670, C═O/NH def on C═N 1615, 1535, 1515. uv (EtOH): 227(21,650;, 327 (28,250).

c. Dimethyl10-chloro-1,4,6,9-tetrahydro-5-methyl-4,6-dioxopyrido[3,2-g]quinoline-2,8-dicarboxylate

The 1:2 adduct (66.2 grams) is added to refluxing Dowtherm A and thereaction mixture is refluxed for fifteen minutes. The reaction mixtureis allowed to cool to room temperature and the resulting solid collectedby filtration (50.8 grams, melting point 275°-280° dec.). Multiplerecrystallization from chloroform gives a yellow crystalline product(38.8 grams, melting point 278°-80° dec.).

Analysis for: C₁₇ H₁₃ O₆ N₂ Cl Calcd.: C, 54.19; H, 3.48; N, 7.44; Cl,9.41. Found: C, 53.94; H, 3.50; N, 7.26; Cl, 12.61.

uv (EtOH): λ_(max) (ε) 400 sh (7,300), 370 (12,050), 287 sh (18,300),277 sh (20,450), 254 (43,650), 235 sh (18,550), 215 sh (16,950), 209(17,650). ir (Nujol): NH 3360, 3350; ═CH 3060; C═O 1730, 1720.

d. Product

The diester (38.8 grams) is stirred in 1.0 N NaOH (350 ml.). The initialsolid dissolves but a new solid precipitates within a few minutes. Thereaction mixture is diluted to 1.5 l. with water and the pH adjusted topH=4 with 3 N hydrochloric acid. The yellow diacid is collected byfiltration, washed several times with water and then with acetone, anddried in a vacuum oven (38.2 grams).

EXAMPLE 14 --1,4,6,9-Tetrahydro-10-methoxy-4,6-dioxopyrido[3,2-g]quinoline-2,8-dicarboxylicacid a. 2,6-Dinitroanisole

Chlorodinitrobenzene (20.0 grams) is dissolved in anhydrous methanol(100 ml.). Sodium methoxide solution (25% in methanol, 14 ml.) is addedand the mixture stirred at room temperature for eighteen hours. Thereaction mixture is poured into water (500 ml.) and the resultingsolution extracted with ether (3 × 200 ml.). The combined ether extractsare washed with water (100 ml.), and dried with anhydrous sodiumsulfate. Removal of the solvent leaves a solid which gives yellowneedles after Darco treatment and recrystallization from ethanol (11.15gram, melting point 118°).

Analysis for: C₇ H₆ N₂ O₅ Calcd.: C, 42.43; H, 3.05; N, 14.14. Found: C,42.39; H, 3.08; N, 14.13. iv (Nujol): C═C/NO₂ 1610, 1580, 1525; C-O1265, 980. uv (EtOH): λ_(max) (ε) 227 sh (10,300), 300 (1950).

b. Tetramethyl 2,2'-(2-methoxyphenylene-1,3-diimino)dibutenedioate

2,6-Dinitroanisole (10.0 grams) is dissolved in methanol (150 ml.) and5% palladium on charcoal (1.0 gram) added. The mixture is treated withhydrogen at 40 psi on the Parr Hydrogenator until the uptake of hydrogenstops. The catalyst is removed by filtration and dimethylacetylenedicarboxylate (16.0 grams) added slowly to the filtrate. Thereaction mixture is stirred for eighteen hours. The resulting solid(10.3 grams) is collected by filtration. Additional crops (7.9 grams)are obtained from the concentrated filtrate. Recrystallization frommethanol gives yellow crystals (18.0 grams) melting point 105°-110°).

Analysis for: C₁₉ H₂₂ O₉ N₂ Calcd.: C, 54.02; H, 5.25; N, 6.63. Found:C, 53.84; H, 5.17; N, 6.13. ir (Nujol): NH 3240; C═O 1740; aromatic CH790, 780. iv (EtOH): λ_(max) (ε) 224 (20,000), 332 (29,450).

c. Dimethyl1,4,6,9-tetrahydro-10-methoxy-4,6-dioxopyrido[3-2-g]quinoline-2,8-dicarboxylate

The 1:2 adduct (12 grams) is added carefully to refluxing Dowtherm A(100 ml.). The mixture is heated at reflux for three minutes and thenallowed to cool to room temperature. The solid precipitate (7.94 grams)is collected and washed with acetone. Recrystallization frommethanol-chloroform gives yellow crystals (melting point 291° dec.).

Analysis for: C₂₃ H₃₀ O₈ N₂ Calcd.: C, 56.98; N, 3.94; N, 7.82. Found:C, 57.02; N, 4.08; N, 7.88.

ir (Nujol): NH/OH 3390, 3330, 3250, 1735 C═O or C═N/C═C 1640, 1585,1520.

uv (EtOH): λ_(max) (ε) 218 (18,100), 234, sh (16,800), 257 (50,650), 288sh (14,000), 357 (7,600), 373:11,100), 407 (12,850), 445 sh (2,250).

d. Product

The diester (1.0 gram) is stirred in 1.0 N sodium hydroxide (150 ml.)for ten minutes. The pH of the resulting solution is adjusted to pH=3with concentrated hydrochloric acid. The yellow diacid is collected byfiltration and washed with water (0.69 gram, melting point 305° dec.).

EXAMPLE 15 --10-Fluoro-1,4,6,9-tetrahydro-4,6-dioxopyrido[3,2-g]quinoline-2,8-dicarboxylicacid a. 1-Fluoro-2,6-dinitrobenzene

A mixture of 1-chloro-2,6-dinitrobenzene (30 grams), anhydrous potassiumfluoride (35 grams), and dimethylformamide (50 ml.) is refluxed fortwenty-four hours. The reaction mixture is poured into water (250 ml.)and extracted with ether (3 × 100 ml.). The combined ether extracts aredried with anhydrous sodium sulfate. Removal of the solvent leaves brownsolid. Chromatography of the solid on silica gel with methylene chlorideas the elutant gives a light yellow solid after recrystallization frompentane-methylene chloride. (20.30 grams, melting point 59°). Massspectrum (70 ev) mol. ion 186 m/e.

b. Tetramethyl 2,2'(2-fluorophenylenediimino)-dibutenedioate

1-Fluoro-2,6-dinitrobenzene (15 grams) in methanol (300 ml.) is treatedwith 10% palladium on charcoal (1.5 gram) and hydrogen (40 psi) on aParr Hydrogenator until hydrogen uptake ceases. The solvent is removedon a small aliquot to leave a colorless oil. Since this oil does notcrystallize easily, the remaining solution is used directly. Dimethylacetylenedicarboxylate (25 grams) is added to the hydrogenated solutionand the resulting mixture stirred for four hours. The yellow 1:2 adductis collected by filtration (18.8 grams, melting point 170°-174°).Recrystallization from methanol gives yellow crystals.

Analysis for: C₁₈ H₁₉ O₈ N₂ F Calcd.: C, 52.68; H, 4.67; N, 6.83; F,4.63. Found: C, 52.53; H, 4.72; N, 6.99; F, 3.27. ir (Nujol): NH 3290;C═O 1735, 1670; C-O/C-F/C-N/ 1275, 1220, 1190, 1140, 1030. uv (EtOH):λ_(max) (ε) 219 (18,400), 245 sh (10,950), 327 (29,800).

c. Dimethyl10-fluoro-1,4,6,9-tetrahydro-4,6-dioxopyrido[3,2-g]quinoline-2,8-dicarboxylate

The 1:2 adduct (15 grams) is added to refluxing Dowtherm A and refluxedfor four minutes. A yellowish solid precipitates from the reactionmixture as it cools. This solid is collected by filtration (7.05 grams,melting point 310°-319° dec.)

d. Product

The diester (1.0 gram) is stirred in 1.0 N sodium hydroxide (35 ml.) forone hour. The reaction mixture is added to 50 ml. of water and the pH ofthe resulting solution adjusted to pH=3 with concentrated hydrochloricacid. The diacid is collected by filtration, washed with acetone, anddried in a vacuum oven (0.95 gram).

EXAMPLE 16 --1,4,6,9-Tetrahydro-3,7-10-trimethyl-4,6-dioxopyrido[3,2-g]quinoline-2,8-dicarboxylicacid a. Tetramethyl 2,2'-dimethyl-3,3'-(2-methylphenylene)dibutenedioate

A mixture of 2,6-diaminotoluene (10 grams), benzene (250 ml.), diethyloxalpropionate and 0.5 gram p-toluenesulfonic acid is refluxed foreighteen hours with constant water removal. A small amount of yellowsolid (0.5 gram) precipitates from the cooled reaction mixture to leavea reddish oil which crystallizes when trituated with methanol (12.2grams). The 1:2 adduct is recrystallized from methanol to give yellowcrystals (melting point 90°).

Analysis for: C₂₅ H₃₄ O₈ N₂ Calcd.: C, 61.22; H, 6.94; N, 5.71. Found:C, 60.79; H, 7.00; N, 5.66. ir (Nujol): NH 3220, 3170; C═O 1725;aromatic CH 770. uv (EtOH): λ_(max) (ε) 228 (11,150), 246 sh (9,500),328 (28,850).

b. Diethyl1,4,6,9-tetrahydro-3,7-10-trimethyl-4,6-dioxopyrido[3,2-g]quinoline-2,8-dicarboxylate

The 1:2 adduct (10 grams) is added to refluxing Dowtherm A (125 ml.) andrefluxed for five minutes. The mixture is allowed to cool to roomtemperature and the resulting diester collected by filtration (8.1grams, melting point 248°-255°).

Analysis: ir (Nujol): NH/OH 3490, 3430, 3380, 3250, 3170; NH/═CH 3090;C═O 1740, 1700.

uv (EtOH): λ_(max) (ε) 208 (16,200), 218 (16,650), 263 (64,250), 293 sh(11,400), 383 (11,000), 405 sh (9,100).

c. Product

The diester (6.0 grams) is stirred in 1.0 N NaOH (100 ml.) until thesolid dissolves (ca. 0.5 hr). The reaction mixture is poured into water(100 ml.) and the pH adjusted to pH=3 with concentrated hydrochloricacid. The diacid is collected as a yellow solid, washed sequentiallywith water and acetone, and dried in a vacuum oven (5.29 grams).

EXAMPLE 17 --10-Cyano-1,4,6,9-tetrahydro-4,6-dioxopyrido(3,2-g)quinoline-2,8-dicarboxylicacid a. 2,6-Dinitrobenzonitrile

1-Chloro-2,6-dinitrobenzene (40.4 grams) is dissolved in anhydrousdimethylformamide (200 ml.). Cuprous cyanide (72 grams) is added and thestirred reaction mixture is heated to reflux for six hours. The darkbrown reaction mixture is cooled and poured into water (1.5 l.) withstirring. The tan precipitate is collected by filtration and thenextracted three times with hot ethanol (300 ml.). Removal of two-thirdsof the solvent from combined ethanol extracts under reduced pressuregives a tan precipitate. The precipitate is collected by filtration andrecrystallized from ethanol to give a tan product (7.2 grams) melting at143°-146.5°.

b. 2,6-Diaminobenzonitrile

2,6-Dinitrobenzonitrile (10.0 grams) is added in portions to a stirredsolution of stannous chloride (82.5 grams) in concentrated HCl (230 ml.)at room temperature. Stirring is continued at room temperature for twoand one-half hours, then the reaction mixture is cooled to 0° and madestrongly basic with 50% NaOH. The reaction mixture is diluted with water(1 l.) and extracted four times with methylenechloride (200 ml.). Thecombined extracts are washed once with water (200 ml.), dried oversodium sulfate, then taken to dryness under reduced pressure.Recrystallization of the crude solid (4.6 grams) frombenzene-Skellysolve "B" gives the product (4.15 grams) melting at91°-92°.

c. Tetramethyl 2,2'-(2-cyano-phenylene-1,3-diimino)dibutenedioate

Dimethylacetylene dicarboxylate (9.5 grams) is added dropwise to astirred solution of 2,6-diaminobenzonitrile (4.0 grams) in methanol (50ml.) at room temperature. The reaction mixture is stirred at roomtemperature for eighteen hours, during which time the yellow product, a1:2 adduct, precipitates and is collected by filtration (5.15 grams),melting point 160°-210°. Recrystallization from acetone gives a material(2.43 grams) melting at 218°-220° (dec.). Additional crops totaling 7.5grams are obtained from the methanol filtrate when stirred for 72 hoursat room temperature.

d. Dimethyl10-cyano-1,4,6,9-tetrahydro-4,6-dioxopyrido[3,2-g]quinoline-2,8-dicarboxylate

The 1:2 adduct (1.0 gram) is added to refluxing Dowtherm A (ca. 250°)and the mixture heated at reflux for ten minutes. Upon cooling, the tancrystalline product precipitates (0.70 gram), melting point 282° (dec.).Chromatography on silica gel gives the pure yellow product (0.42 gram)melting point 281°-283° (dec.).

Analysis for: C₁₇ H₁₁ O₆ N₃ Calcd.: C, 57.79; H, 3.14; N, 11.90. Found:C, 58.13; H, 3.23; N, 12.11.

e. Product

The dimethyl ester (0.40 gram) is dissolved in 1M NaOH (15 ml.) andstirred at room temperature for one-half hour. The solution is acidifiedwith 3M HCl to give the desired diacid as a yellow crystalline solid.The product is collected by filtration, washed with water and dried atreduced pressure at 60° (0.35 gram), melting point >320°.Recrystallization of 50 mg. from water gives a material with a meltingpoint >320°.

Analysis for: C₁₅ H₇ O₆ N₃.1/2H₂ O Calcd.: C, 53.90; H, 2.41; N, 12.57.Found: C, 54.24; H, 2.14; N, 12.65.

EXAMPLE 18 --5-Methyl-1,4,6,9-tetrahydro-4,6-dioxopyrido[3,2-q]quinoline-2,8,-10-tricarboxylicacid a. Methyl 2,6-dinitrobenzoate

2,6-Dinitrotoluic acid (10. gram) is suspended in ether (125 ml.) at 0°C. 1-Methyl-3-p-tolyltriazene (8.2 grams) in ether (75 ml.) is addeddropwise to the stirred reaction mixture in an ice bath. The reactionmixture is stirred at 0° for one hour and at room temperature for onehour. The reaction mixture is diluted to 1 l. with ether and theinsoluble product collected by filtration. Recrystallization frommethanol gives a crystalline solid.

b. Tetramethyl 2,2'-(2-carboxymethoxy-5-methylphenylene-1,3-diimino)dibutenedioate

Methyl 2,6-dinitrotoluate (7.75 grams) is dissolved in methanol (250ml.) and treated with 10% palladium on charcoal (0.8 gram) and hydrogen(40 psi) on a Parr Hydrogenator for two hours. The catalyst is removedby filtration and dimethyl acetylenedicarboxylate (15.0 grams) is addedslowly. The reaction mixture is allowed to stir at room temperature foreighteen hours. The 1:2 adduct is collected by filtration.

c. Trimethyl1,4,6,9-tetrahydro-5-methyl-4,6-dioxopyrido[3,2-q]quinoline-2,8,-10-tricarboxylate

The 1:2 adduct (10.0 grams) is added to refluxing Dowtherm A. Thereaction mixture is refluxed for seven minutes and then allowed to coolto room temperature. The triester is collected by filtration and washedwith acetone and twice with hot chloroform. The insoluble solid ishomogenous by thin layer chromotography.

d. Product

The triester (1.0 gram) is dissolved in 1.0 N sodium hydroxide (15 ml.).After stirring for a few minutes, the sodium salt precipitates. Thissolid is collected and dissolved in water and the pH is adjusted to pH =3 with 3M hydrochloric acid. The solid diacid is collected byfiltration, washed with water and dried in a vacuum oven.

EXAMPLE 19 --10-Cyano-1,4,6,9-tetrahydro-5-methyl-4,6-dioxopyrido[3,2-q]quinoline-2,8-dicarboxylicacid a. 2,6-Diamino-p-tolunitrile

2,6-Dinitro-p-tolunitrile (10 grams) is added in portions to a stirredsolution of stannous chloride (82.5 grams) in concentrated HCl (230 ml.)at room temperature. Stirring is continued at room temperature for twoand one-half hours. The reaction mixture is cooled to 0° and madestrongly basic with 50% NaOH. The reaction mixture is diluted with water(1 l.) and extracted four times with methylene chloride (200 ml.). Thecombined extracts are washed once with water (200 ml.), dried oversodium sulfate and then taken to dryness under reduced pressure.Recrystallization of the crude solid from benzene-Skellysolve "B" gives2,6-diaminotolunitrile.

b. Tetramethyl 2,2'-(2-cyano-5-methylphenylene-1,3-diimino)dibutenedioate

Dimethylacetylene dicarboxylate (9.5 grams) is added dropwise to astirred solution of 2,6-diaminotolunitrile (4.0 grams) in methanol (50ml.) at room temperature. The reaction mixture is stirred at roomtemperature for forty-eight hours during which time the productprecipitates and is collected by filtration. Recrystallization fromacetone gives the 1:2 adduct.

c. Dimethyl10-cyano-1,4,6,9-tetrahydro-5-methyl-4,6-dioxopyrido[3,2-q]quinoline-2,8-dicarboxylate

Tetramethyl 2,2'-(2-cyano-5-methylphenylene-1,3-diimino)-dibutenedioate(1.0 gram) is added to refluxing Dowtherm A (ca. 250°) and the mixtureheated at reflux for ten minutes. Upon cooling, the crystalline productprecipitates. Chromatography on silica gel gives the pure product.

d. Product

The dimethyl ester (0.40 gram) is dissoled in 1M NaOH (15 ml.) andstirred at room temperature for one-half hour. The solution is acidifiedwith 3M HCl to give the desired diacid as a crystalline solid. Theproduct is collected by filtration, washed with water and dried atreduced pressure at 60°.

EXAMPLE 20 -- Tris(hydroxymethyl)aminomethane (THAM) salts of Examples11-19

The tris(hydroxymethyl)aminomethane salts of the products of Examples11-19 are prepared by dissolving the acid in aqueoustris(hydroxymethyl)aminomethane. Methanol is added to the solution andthe precipitate is collected.

The compositions of the present invention are presented foradministration to humans and animals in unit dosage forms, such astablets, capsules, pills, powders, granules, sterile parenteralsolutions or suspensions, and oral solutions or suspensions, andoil-in-water and water-in-oil emulsions containing suitable quantitiesof the compound of Formula Ia. The preferred method of administration isby inhalation into the lung by means of an aerosol liquid or powder forinsufflation. A preferred dosage schedule for repeated administration ofthe compounds of this invention is disclosed in a later portion of thisspecification.

For oral administration either solid or fluid unit dosage forms can beprepared. For preparing solid compositions such as tablets, the compoundof Formula Ia is mixed with conventional ingredients such as talc,magnesium stearate, dicalcium phosphate, magnesium aluminum silicate,calcium sulfate, starch, lactose, acacia, methylcellulose, andfunctionally similar materials as pharmaceutical diluents or carriers.Capsules are prepared by mixing the compound with an inertpharmaceutical diluent and filling the mixture into a hard gelatincapsule of appropriate size. Soft gelatin capsules are prepared bymachine encapsulation of a slurry of the compound with an acceptablevegetable oil, light liquid petroleum or other inert oil.

Fluid dosage forms for oral administration such as syrups, elixirs, andsuspensions can be prepared. The water-soluble forms can be dissolved inan aqueous vehicle together with sugar, aromatic flavoring agents andpreservatives to form a syrup. An elixir is prepared by using ahydro-alcoholic (ethanol) vehicle with suitable sweeteners such as sugarand saccharin, together with an aromatic flavoring agent.

Suspensions can be prepared with an aqueous vehicle with the aid of asuspending agent such as acacia, tragacanth, methylcellulose and thelike.

For parenteral administration, fluid dosage forms are prepared utilizingthe compound and a sterile vehicle, water being preferred. The compound,depending on the vehicle and concentration used, can be either suspendedor dissolved in the vehicle. In preparing solutions the compound can bedissolved in water for injection and filter sterilized before fillinginto a suitable vial or ampul and sealing. Advantageously, adjuvantssuch as a local anesthetic, preservative and buffering agents can bedissolved in the vehicle. To enhance the stability, the composition canbe frozen after filling into the vial and the water removed undervacuum. The dry lyophilized powder is then sealed in the vial and anaccompanying vial of water for injection is applied to reconstitute theliquid prior to use. Parenteral suspensions are prepared insubstantially the same manner except that the compound is suspended inthe vehicle instead of being dissolved and sterilization cannot beaccomplished by filtration. The compound can be sterilized by exposureto ethylene oxide before suspending in the sterile vehicle.Advantageously, a surfactant or wetting agent is included in thecomposition to facilitate uniform distribution of the compound.

Additionally, a rectal suppository can be employed to deliver the activecompound. This dosage form is of particular interest where the mammalcannot be treated conveniently by means of other dosage forms, such asorally or insufflation, as in the case of young children or debilitatedpersons. The active compound can be incorporated into any of the knownsuppository bases by methods known in the art. Examples of such basesinclude cocoa butter, polyethylene glycols (Carbowaxes), polyethylenesorbitan monostearate, and mixtures of these with other compatiblematerials to modify the melting point or dissolution rate. These rectalsuppositories can weigh from about 1 to 2.5 Gm.

The preferred compositions are those adapted for inhalation into thelung and containing a compound of the invention which is water-soluble.For treatment of allergic conditions of the nose, such as rhinitis,compositions adapted for contact with nasal linings are preferred.

Compositions for inhalation are of three basic types: (1) a powdermixture preferably micropulverized; (2) an aqueous solution to besprayed with a nebulizer; and (3) an aerosol with volatile propellant ina pressurized container.

The powders are quite simply prepared by mixing a compound of theformula with a solid base which is compatible with lung tissue,preferably lactose. The powders are packaged in a device adapted to emita measured amount of powder when inhaled through the mouth.

Aqueous solutions are prepared by dissolving the compound of the Formula1a in water and adding salt to provide an isotonic solution andbuffering to a pH compatible with inhalation. The solutions aredispersed in spray device or nebulizer and sprayed into the mouth whileinhaling.

Aerosols are prepared by dissolving a compound of the Formula 1a inwater or ethanol and mixing with a volatile propellant and placing in apressurized container having a metering valve to release a predeterminedamount of material.

The liquefied propellant employed is one which has a boiling point below65° F. at atmospheric pressure. For use in compositions intended toproduce aerosols for medicinal use, the liquefied propellant should benon-toxic. Among the suitable liquefied propellants which may beemployed are the lower alkanes containing up to five carbon atoms, suchas butane and pentane, or a lower alkyl chloride, such as methyl, ethyl,or propyl chlorides. Further suitable liquefied propellants are thefluorinated and fluorochlorinated lower alkanes such as are sold underthe trademarks "Freon" and "Genetron". Mixtures of the above-mentionedpropellants may suitably be employed. Examples of these propellants aredichlorodifluoromethane ("Freon 12"), dichlorotetrafluoroethane ("Freon114"), trichloromonofluoromethane ("Freon 11"),dichloromonofluoromethane ("Freon 21"), monochlorodifluoromethane("Freon 22"), trichlorotrifluoroethane ("Freon 113"), difluoroethane("Genetron 142-A") and monochlorotrifluoromethane ("Freon 13").

The term "unit dosage form", as used in the specification and claims,refers to physically discrete units suitable as unitary dosages forhuman subjects and animals, each unit containing a predeterminedquantity of active material calculated to produce the desiredtherapeutic effect in association with the required pharmaceuticaldiluent, carrier or vehicle. The specifications for the novel unitdosage forms of this invention are dictated by and directly dependent on(a) the unique characteristics of the active material and the particulareffect to be achieved and (b) the limitations inherent in the art ofcompounding such an active material for use in humans and animals, asdisclosed in detail in this specification, these being features of thepresent invention. Examples of suitable unit dosage forms in accord withthis invention are tablets, capsules, pills, suppositories, powderpackets, wafers, granules, cachets, teaspoonfuls, tablespoonfuls,droperfuls, ampuls, vials, aerosols with metered discharges, segregatedmultiples of any of the foregoing, and other forms as herein described.

An effective but non-toxic quantity of the compound is employed intreatment. The dosage of the compound for treatment depends on the routeof administration. A dosage schedule of from about 0.01 to about 50 mg.of compound in a single dose administered parenterally or by inhalationin the compositions of this invention is effective for preventingallergy attacks. More specifically, the single dose is from about 0.01to about 10 mg. of compound. The oral and rectal dose is from about 0.1to about 500 mg. in a single dose. More specifically, the single dose isfrom about 0.1 to about 50 mg. of compound. The dosage to beadministered can be repeated up to four times daily. However, when it isnecessary to repeat treatment, a preferred dosage schedule reduces thesecondary treatment dosage to from about 0.5 percent to about 20 percentof the above dosages, more specifically, from about 1 to about 10percent of the above dosages. In this manner, a state of allergyprophylaxis can be maintained. The reduced dosage is taken until thatdosage no longer provides effective protection. At that time, the largerdosage is repeated, followed by the reduced dosage. An example of such adosage schedule is the following: An asthmatic individual insufflates1.0 mg. of the tris(hydroxymethyl)aminomethane salt of10-chloro-1,4,6,9-tetrahydro-5-methyl-4,6-dioxopyrido[3,2-g]quinoline2,8-dicarboxylicacid. Four hours later the individual insufflates 0.02 mg. of the samecompound and every four to six hours thereafter insufflates 0.02 mg. ofthe same compound until effective asthma prophylaxis is not provided.The individual then insufflates 1.0 mg. mg. of the same compound, thenreduces the insufflation dosage to 0.02 mg. four to six hours later. Thedosage schedule continues in this manner.

The administration of the compositions of the present invention tohumans and animals provides a method for the prophylactic treatment ofallergy or all analphylactic reactions of a reagin or a non-reaginmediated nature. That is to say these compositions, when administered toa sensitized individual prior to the time that the individual comes intocontact with substances (antigens) to which he is allergic, will preventthe allergic reaction which would otherwise occur.

For example, the process can be used for prophylactic treatment of suchchronic conditions as bronchial asthma, allergic rhinitis, food allergy,hay fever, urticaria, auto-immune diseases, exercise induced asthma,stress induced asthma, and bird fancier's disease.

EXAMPLE 21

A lot of 10,000 tablets, each containing 0.1 mg. of dimethyl10-chloro-1,4,6,9-tetrahydro-4,6-dioxopyrido[3,2-g]quinoline-2,8-dicarboxylateis prepared from the following types and amounts of ingredients:

    ______________________________________                                        Dimethyl 10-chloro-1,4,6,9-                                                   tetrahydro-4,6-dioxopyrido-                                                   [3,2-g]quinoline-2,8-                                                         dicarboxylate           1 Gm.                                                 Dicalcium phosphate     1,500 Gm.                                             Methylcellulose, U.S.P. (15 cps.)                                                                     60 Gm.                                                Talc                    150 Gm.                                               Corn starch             200 Gm.                                               Magnesium stearate      12 Gm.                                                ______________________________________                                    

The compound and dicalcium phosphate are mixed well, granulated with 7.5percent solution of methylcellulose in water, passed through a No. 8screen and dried carefully. The dried granules are passed through a No.12 screen, mixed thoroughly with the talc, starch and magnesiumstearate, and compressed into tablets.

These tablets are useful in preventing hay fever attacks at a dose of 1tablet every four hours.

EXAMPLE 22

One thousand two-piece hard gelatin capsules, each containing 100 mg. ofdimethyl10-chloro-1,4,6,9tetrahydro-4,6-dioxopyrido[3,2-g]quinoline-2,8-dicarboxylateare prepared from the following types and amounts of ingredients:

    ______________________________________                                        Dimethyl 10-chloro-1,4,6,9-                                                   tetrahydro-4,6-dioxopyrido-                                                   [3,2-g]quinoline-2,8-dicarbox-                                                ylate, micronized       100 Gm.                                               Talc                    100 Gm.                                               Magnesium stearate      1 Gm.                                                 ______________________________________                                    

The ingredients are mixed well and filled into capsules of the propersize.

Capsules so prepared are useful in preventing attacks of bronchialasthma at a dose of one capsule every six hours.

EXAMPLE 23

One thousand tablets, each containing 500 mg. of dimethyl10-chloro-1,4,6,9-tetrahydro-4,6-dioxopyrido-[3-2-g]quinoline-2,8-dicarboxylateare made from the following types and amounts of ingredients:

    ______________________________________                                        Dimethyl 10-chloro-1,4,6,9-                                                   tetrahydro-4,6-dioxopyrido-                                                   [3,2-g]quinoline-2,8-                                                         dicarboxylate           500 Gm.                                               Microcrystalline cellulose NF                                                                         120 Gm.                                               Starch                  16 Gm.                                                Magnesium stearate powder                                                                             4 Gm.                                                 ______________________________________                                    

The ingredients are screened and blended together and pressed into 640mg. tablets.

The tablets are useful to protect against food allergy at a dose of 1tablet before meals.

EXAMPLE 24

A sterile preparation suitable for intramuscular injection andcontaining 1 mg. of dimethyl10-chloro-1,4,6,9-tetrahydroxy-4,6-dioxopyrido[3,2-g]quinoline-2,8-dicarboxylatein each milliliter is prepared from the following ingredients:

    ______________________________________                                        Dimethyl 10-chloro-1,4,6,9-                                                   tetrahydroxy-4,6-dioxopyrido-                                                 [3,2-g]quinoline-2,8-di-                                                      carboxylate             1 Gm.                                                 Benzyl benzoate         200 ml.                                               Methylparaben           1.5 Gm.                                               Propylparaben           0.5 Gm.                                               Cottonseed oil q.s.     1,000 ml.                                             ______________________________________                                    

One milliliter of this sterile preparation is injected for prophylactictreatment of allergic rhinitis.

EXAMPLE 25 -- Aqueous Solution

600 ml. of an aqueous solution containing 0.1 mg. of thetris(hydroxymethyl)aminomethane salt of10-chloro-1,4,6,9-tetrahydro-4,6-dioxopyrido[3,2-g]quinoline-2,8-dicarboxylicacid per ml. is prepared as follows:

    ______________________________________                                        Tris(hydroxymethyl)aminomethane                                               salt 10-chloro-1,4,6,9-tetra-                                                 hydro-4,6-dioxopyrido[3,2-g]                                                  quinoline-2,8-dicarboxylic acid                                                                        60 mg.                                               Sodium chloride          5,400 mg.                                            Water for injection q.s. 600 ml.                                              ______________________________________                                    

The THAM salt and sodium chloride are dissolved in sufficient water tomake 600 ml. and sterile filtered.

The solution is placed in nebulizers designed to deliver 0.25 ml. ofsolution per spray.

The solution is sprayed into the lungs every four hours for preventionof asthmatic attacks.

EXAMPLE 26 -- Powder for Insufflation

A powder mixture consisting of 100 mg. oftris-(hydroxymethyl)aminomethane salt of10-chloro-1,4,6,9-tetrahydro-4,6-dioxopyrido[3,2-g]quinoline-2,8-dicarboxylicacid and sufficient lactose to make 5 gm. of mixture is micropulverizedand placed in an insufflator designed to deliver 50 mg. of powder perdose.

The powder is inhaled into the lungs for prevention of asthmaticattacks.

The powder is inhaled into a nostril of the nose every four to six hoursfor prevention of rhinitis.

EXAMPLE 27 -- Aerosol

Twelve grams of an aerosol composition is prepared from the followingingredients:

    ______________________________________                                        Tris(hydroxymethyl)aminomethane salt of                                       10-chloro-1,4,6,9-tetrahydro-4,6-dioxo-                                       pyrido[3,2-g]quinoline-2,8-dicarboxylic                                       acid                    0.015 Gm.                                             Freon 12                1.450 Gm.                                             Freon 114               2.160 Gm.                                             Water                   7.775 Gm.                                             Sorbitan monoleate      0.600 Gm.                                             ______________________________________                                    

The THAM salt is dissolved in water, chilled to -30° C., and added tothe chilled Freons. The 12 grams of composition is added to a 13 cc.plastic coated bottle and capped with a metering valve, which releases80 mg. of composition in an aerosol. The aerosol is inhaled every sixhours for prevention of asthmatic attacks.

EXAMPLE 28

In individuals who require continual treatment in the Examples 21through 27, the dosage of the Example is given initially and eachsucceeding administration of the drug is at 1/50 of the initial dosage.This maintenance dosing is continued until effective allergy prophylaxisis not obtained. The initial dosage of Examples 21 through 27 is thenstarted once more, followed by the maintenance dosages.

EXAMPLE 29

After allowing for the differing solubilities of the compounds and theactivity of the particular compound as measured, for example, by the invivo rat passive cutaneous anaphylaxis assay, a suitable quantity ofeach of the compounds of Tables II, III and IV and particularly thecompounds of this invention in Examples 11-19 are substituted for theactive compound in the compositions and uses of Examples 21 through 27.Results showing antiallergy activity are obtained.

EXAMPLE 30

The rat passive cutaneous anaphylaxis assay is run in the followingmanner:

Female Sprague-Dawley 250 gm. rats are skin-sensitized with ratanti-ovalbumin homocytotropic antibody that is heat labile and has apassive cutaneous anaphylaxis titer of 1:128. After a 72-hour latencyperiod, the animals are challenged i.v. with 4 mg. ovalbumin (OA) +5 mg.Evans blue dye and the test compound. Thirty minutes later theextravascular bluing that results from antigen antibody combination atthe skin site is read. Antibody dilutions are used such that in controlanimals a 4 mm spot is the lowest detectable spot, and 4 or 5 lowerdilutions are used to give a range of antibody in each animal. Four tofive animals are used for each variable in the experiment. Percentinhibition of the PCA assay is calculated by comparing the spot scoresof treated rats with the spot scores of control rats. The spot score isthe total number of detectable spots over the number of animals.

The tris(hydroxymethyl)aminomethane salt of the following compounds areprepared by dissolving the carboxylic acid in an equivalent weight ofaqueous tris(hydroxymethyl)aminomethane and is tested in the rat passivecutaneous anaphylaxis assay in the above manner.

The inhibitory dose₅₀ for the tris(hydroxymethyl)-aminomethane salts ofcompounds of the invention, when given i.v., are the following

    ______________________________________                                                               Inhibitory                                             THAM salt of           Dose.sub.50 mg./kg.                                    ______________________________________                                        1,4,6,9-Tetrahydro-10-methoxy-4,6-dioxo-                                      pyrido[3,2-g]quinoline-2,8-dicarboxylic                                       acid                   0.05                                                   10-Cyano-1,4,6,9-tetrahydro-4,6-dioxo-                                        pyrido[3,2-g]quinoline-2,8-dicarboxylic                                       acid                   0.05                                                   10-Fluoro-1,4,6,9-tetrahydro-4,6-dioxo-                                       pyrido[3,2-g]quinoline-2,8-dicarboxylic                                       acid                   0.10                                                   1,4,6,9-Tetrahydro-4,6-dioxopyrido[3,2-g]-                                    quinoline-2,8,10-tricarboxylic acid                                                                  0.1                                                    10-Chloro-1,4,6,9-tetrahydro-4,6-dioxo-                                       5-(trifluoromethyl)pyrido[3,2-g]quinoline-                                    2,8-dicarboxylic acid  0.5                                                    10-Chloro-1,4,6,9-tetrahydro-5-methyl-                                        4,6-dioxopyrido[3,2-g]quinoline-2,8-di-                                       carboxylic acid        0.01                                                   ______________________________________                                    

Amine cations within the scope of the subject invention arepharmaceutically acceptable amine cations in the compounds of thisinvention. Amines previously exemplified earlier in the specificationare suitable and preferred. Additional suitable amines include aminesselected from the group consisting of H₂ NR', HNR₂ ' and NR₃ ', where R'is selected from the group consisting of alkyl from one to three carbonatoms, and --CH₂ CH₂ OH.

Additional pharmaceutically acceptable metals include the alkaline earthmetals such as calcium and magnesium and other metals such as aluminum.

Another sub genus of this invention are compounds where Z is hydrogen, Ris selected from the group consisting of hydrogen and a pharmaceuticallyacceptable metal or amine cation, X is selected from the groupconsisting of cyano and ##STR15## where Q is selected from the groupconsisting of hydrogen and a pharmaceutically acceptable metal or aminecation and Q is the same as R; and Y is selected from the groupconsisting of hydrogen, alkyl from one to four carbon atoms, inclusive,halogen and alkoxy of from one to four carbon atoms, inclusive. Afurther sub genus of the invention are compounds where Z is hydrogen, Ris selected from the group consisting of hydrogen and a pharmaceuticallyacceptable metal or amine cation, X is selected from the groupconsisting of hydrogen, alkyl from one to four carbon atoms, inclusive,halogen, and alkoxy of from one to four carbon atoms, inclusive, and Yis selected from the group consisting of cyano and ##STR16## where Q isselected from the group consisting of hydrogen and a pharmaceuticallyacceptable metal or amine cation and Q is the same as R.

We claim: 1.Di-tris(hydroxymethyl)methylammonium-10-chloro-1,4,6,9-tetrahydro-5-methyl-4,6-dioxopyrido[3,2g]guinoline-2,8-dicarboxylate.